This is a competitive renewal application for a Level III Research Scientist Award. The candidate has previously been funded with both a Level I (K01) and two Level II (K02) awards to investigate the role of abnormal corticolimbic circuitry in the pathophysiology and treatment of schizophrenia. Using a combination of techniques, i.e., cell counting, high resolution receptor binding autoradiography (HR-RBA), in situ hybridization and immunocytochemistry (ICC), the research described in this proposal is aimed at characterizing changes in the intrinsic neural circuitry of the anterior cingulate cortex (ACCx), prefrontal area (PFCx) and hippocampal formation (HIPP) of schizophrenics and manic depressives (MDs) as compared to normal control (CONs) individuals. The studies will focus on the GABA (Specific Aim I) and glutamate (Specific Aim II) neurotransmitter system and will consider how their interaction with monoaminergic projections to the cortex (Specific Aim III) might be altered in relation to schizophrenia and treatment with neuroleptic drugs. Schizophrenics and MDs with and without neuroleptic exposure will be compared to assess how these agents might be contributing to changes in postmortem brain. All four of these transmitter systems will also be studied in normal teenagers in order to determine whether they are undergoing critical maturational changes during late adolescence and early adulthood (Specific Aim IV). These latter studies will help determine whether normal developmental changes in key corticolimbic regions may serve as a "trigger" for the onset of schizophrenia in individuals who carry the vulnerability for this disorder. Taken together, the various studies described in this proposal may suggest novel treatment strategies that may be applied early in the course of the illness so that the deterioration of functioning that typically occurs during the first 5-10 years may be diminished or possibly even eliminated.